Objective To explore the value of 6-minute walk test (6MWT) combined with serum cytokines in evaluating the prognosis of chronic heart failure (CHF). Methods A total of 82 CHF patients admitted to our hospital from January 2020 to January 2021 were selected as the study subjects. Their clinical data and cardiac function indicators such as left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) class, and serum N-terminal pro-brain natriuretic peptide(NT-proBNP) levels were collected. 6MWT test was conducted on all of them after admission. The serum levels of cytokines, including interleukin-22 (IL-22), tumor necrosis factor-α (TNF-α) and nuclear factor-kappa B (NF-κB) were detected and recorded. SPSS statistics 19.0 was used for data processing. Pearson or Spearman correlation analyses were employed to analyze the correlation of 6MWT results and serum cytokine levels with cardiac function indicators. Receiver operating characteristic (ROC) curve was plotted to assess the predictive values of various indicators for the prognosis of CHF patients. Cox risk proportional regression model was applied to analyze independent risk factors affecting the prognosis. Results During 1-year follow-up, 2 patients were lost. The other patients were divided into event group (n=36) and non-event group (n=44) according to the occurrence of adverse end points. The patients in the event group had significantly shorter 6MWT distance [(301.25±36.78) vs (413.51±42.36) m], and obviously higher serum levels of IL-22 [(643.51±53.69) vs (511.07±60.11) pg/ml], TNF-α [(412.15±56.69) vs (284.55±35.79) ng/L] and NF-κB [(96.67±13.69) vs (70.05±12.57) pg/ml] when compared with those in the non-event group (all P<0.05). Opposite results [6MWT distance:(390.52±45.87) vs (346.47±43.15) m; IL-22:(540.09±60.33) vs (589.01±58.77) pg/ml; TNF-α:(325.21±53.69) vs (352.02±54.77) ng/L; NF-κB:(78.07±10.85) vs (84.04±11.33) pg/ml] were observed in the patients of NYHA class Ⅱ than those of NYHA class Ⅲ (all P<0.05). Correlation analysis showed that 6MWT result was positively correlated with LVEF in the CHF patients (r=0.511, P<0.001), and negatively with NYHA class (r=-0.405, P=0.012) and serum NT-proBNP level (r=-0.456, P<0.001); serum IL-22 level was negatively correlated with LVEF (r=-0.383, P=0.016) and positively with NT-proBNP level (r=0.296, P=0.037); serum TNF-α level was negatively correlated with LVEF (r=-0.425, P=0.008), and positively with NYHA class (r=0.305, P=0.030) and serum NT-proBNP level (r=0.377, P=0.017); Serum NF-κB level was negatively correlated with LVEF (r=-0.317, P=0.028), and positively with NYHA class (r=0.304, P=0.031) and serum NT-proBNP level (r=0.246, P=0.043). The TNF-α level was negatively correlated with 6MWT result (r=-0.369, P=0.018), and positively with serum IL-22 (r=0.413, P=0.010) and NF-κB levels (r=0.356, P=0.021). ROC curve analysis found that the area under the curve of combined 6MWT result and serum TNF-α and NF-κB for predicting poor prognosis in CHF patients was 0.991 (95%CI 0.939-1.000), with a sensitivity of 0.972, and a specificity of 0.977, and all these values were superior to those of a single indicator. Cox risk proportional regression analysis indicated that 6MWT result and serum TNF-α level were independent risk factor for adverse end points in CHF patients within 1 year after discharge. Conclusion 6MWT result combined with TNF-α, IL-22 and NF-κB levels shows good predictive value for the prognosis of CHF patients.